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The American Journal of Surgical... Aug 2020Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and...
Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.
Topics: Biopsy; Carcinoma; Carcinoma, Ductal; Consensus; Humans; Male; Neoplasm Grading; Neoplasm Invasiveness; Pathology, Clinical; Predictive Value of Tests; Prostatic Neoplasms; Urology
PubMed: 32459716
DOI: 10.1097/PAS.0000000000001497 -
Current Oncology Reports Jan 2021Neuroendocrine prostate cancer (NEPC) is an aggressive histologic subtype of prostate cancer that most commonly arises in later stages of prostate cancer as a mechanism... (Review)
Review
PURPOSE OF REVIEW
Neuroendocrine prostate cancer (NEPC) is an aggressive histologic subtype of prostate cancer that most commonly arises in later stages of prostate cancer as a mechanism of treatment resistance. The poor prognosis of NEPC is attributed in part to late diagnosis and a lack of effective therapeutic agents. Here, we review the clinical and molecular features of NEPC based on recent studies and outline future strategies and directions.
RECENT FINDINGS
NEPC can arise "de novo" but most commonly develops as a result of lineage plasticity whereby prostate cancer cells adopt alternative lineage programs as a means to bypass therapy. Dependence on androgen receptor (AR) signaling is lost as tumors progress from a prostate adenocarcinoma to a NEPC histology, typically manifested by the downregulation of AR, PSA, and PSMA expression in tumors. Genomic analyses from patient biopsies combined with preclinical modeling have pointed to loss of tumor suppressors RB1 and TP53 as key facilitators of lineage plasticity. Activation of oncogenic drivers combined with significant epigenetic changes (e.g., EZH2 overexpression, DNA methylation) further drives tumor proliferation and expression of downstream neuronal and neuroendocrine lineage pathways controlled in part by pioneer and lineage determinant transcription factors (e.g., SOX2, ASCL1, BRN2). These biologic insights have provided a framework for the study of this subgroup of advanced prostate cancers and have started to provide rationale for the development of biomarker-driven therapeutic strategies. Further study of the dynamic process that leads to NEPC is required for the development of effective strategies to identify and treat patients developing lineage plasticity as a mechanism of treatment resistance.
Topics: Carcinoma, Neuroendocrine; Disease Progression; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms
PubMed: 33433737
DOI: 10.1007/s11912-020-01003-9 -
European Journal of Cancer (Oxford,... Nov 2019Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may arise de novo or in patients previously treated with hormonal therapies for...
BACKGROUND
Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may arise de novo or in patients previously treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. Despite being important to recognise, the clinical features of NEPC are poorly defined and could help guide when to perform a biopsy to look for NEPC histologic transformation.
METHODS
We reviewed baseline, treatment and outcome data of 87 patients with metastatic prostate cancer and tumour biopsy confirming NEPC histology. Forty-seven (54.0%) NEPC cases presented de novo, and 40 (46.0%) were therapy-related (t-NEPC). Thirty-six (41.4%) were classified as pure small-cell carcinoma, and 51 (58.6%) demonstrated mixed features with both small-cell carcinoma and adenocarcinoma present. Genomic data were available for 47 patients.
RESULTS
The median age at time of NEPC was 68.1 years, median prostate-specific antigen (PSA) was 1.20 ng/ml (0.14 ng/mL small-cell carcinoma, 1.55 ng/mL mixed carcinoma) and sites of metastases included bone (72.6%), lymph node (47.0%), and viscera (65.5%). Median time from adenocarcinoma to t-NEPC diagnosis was 39.7 months (range, 24.5-93.8) with a median of two lines of prior systemic therapy. Platinum chemotherapy was used to treat 57.5% of patients, with a median progression-free survival of 3.9 months. Small-cell carcinoma was associated with worse overall survival (OS) than mixed histology (8.9 months from NEPC diagnosis versus 26.1 months, P < 0.001). Median OS of de novo NEPC was shorter than that of t-NEPC (16.8 months from prostate cancer diagnosis versus 53.5 months, P = 0.043). An average PSA rise per month of ≤0.7 ng/ml before t-NEPC; elevated lactate dehydrogenase levels, RB1 and TP53 loss and liver metastases were poor prognostic features.
CONCLUSIONS
We describe the clinical features of a cohort of patients with NEPC. These characteristics may inform future diagnostic strategies.
Topics: Adenocarcinoma; Aged; Biopsy; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Cohort Studies; Disease Progression; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Prostatic Neoplasms; Retrospective Studies; Survival Analysis; Treatment Outcome
PubMed: 31525487
DOI: 10.1016/j.ejca.2019.08.011 -
International Journal of Molecular... Jan 2021Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine produced from the essential amino acid tryptophan. Serotonin's role as a neurotransmitter in the central... (Review)
Review
Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine produced from the essential amino acid tryptophan. Serotonin's role as a neurotransmitter in the central nervous system and a motility mediator in the gastrointestinal tract has been well defined, and its function in tumorigenesis in various cancers (gliomas, carcinoids, and carcinomas) is being studied. Many studies have shown a potential stimulatory effect of serotonin on cancer cell proliferation, invasion, dissemination, and tumor angiogenesis. Although the underlying mechanism is complex, it is proposed that serotonin levels in the tumor and its interaction with specific receptor subtypes are associated with disease progression. This review article describes serotonin's role in cancer pathogenesis and the utility of the serotonin pathway as a potential therapeutic target in cancer treatment. Octreotide, an inhibitor of serotonin release, is used in well-differentiated neuroendocrine cancers, and the tryptophan hydroxylase (TPH) inhibitor, telotristat, is currently being investigated in clinical trials to treat patients with metastatic neuroendocrine tumors and advanced cholangiocarcinoma. Several in vitro studies have shown the anticancer effect of 5-HT receptor antagonists in various cancers such as prostate cancer, breast cancer, urinary bladder, colorectal cancer, carcinoid, and small-cell lung cancer. More in vivo studies are needed to assess serotonin's role in cancer and its potential use as an anticancer therapeutic target. Serotonin is also being evaluated for its immunoregulatory properties, and studies have shown its potential anti-inflammatory effect. Therefore, it would be of interest to explore the combination of serotonin antagonists with immunotherapy in the future.
Topics: Antineoplastic Agents, Hormonal; Carcinoma, Neuroendocrine; Cell Movement; Cell Proliferation; Cholangiocarcinoma; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Neovascularization, Pathologic; Octreotide; Phenylalanine; Pyrimidines; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Signal Transduction; Tryptophan Hydroxylase; Tumor Cells, Cultured
PubMed: 33525332
DOI: 10.3390/ijms22031268 -
Pathologica Feb 2022In 2022, after a six-year interval, the International Agency for Research on Cancer (IARC) has published the 5th edition of the WHO Classification of Urinary and Male... (Review)
Review
In 2022, after a six-year interval, the International Agency for Research on Cancer (IARC) has published the 5th edition of the WHO Classification of Urinary and Male Genital Tumors, which provides a comprehensive update on tumor classification of the genitourinary system. This review article focuses on prostate carcinoma and underscores changes in the prostate chapter as well as those made across the entire series of the 5th edition of WHO Blue Books. Although no major alterations were made to this chapter, some of the most notable updates include restructure of contents and introduction of a new format; standardization of mitotic counts, genomic nomenclatures, and units of length; refined definition for the terms "variant", "subtype", and "histologic pattern"; reclassification of prostatic intraepithelial neoplasia (PIN)-like adenocarcinoma as a subtype of prostatic acinar adenocarcinoma; and recognition of treatment-related neuroendocrine prostatic carcinoma as a distinct tumor type. Evolving and unsettled issues related to grading of intraductal carcinoma of the prostate and reporting of tertiary Gleason pattern, the definition and prognostic significance of cribriform growth pattern, and molecular pathology of prostate cancer will also be covered in this review.
Topics: Humans; Male; Prostate; Prostatic Neoplasms; Adenocarcinoma; Prognosis; World Health Organization; Neoplasm Grading
PubMed: 36645399
DOI: 10.32074/1591-951X-822 -
Pathologica Feb 2021Neuroendocrine neoplasms of the appendix, colon and rectum are classified according to the most recent WHO classification as neuroendocrine tumors (NET), neuroendocrine... (Review)
Review
Neuroendocrine neoplasms of the appendix, colon and rectum are classified according to the most recent WHO classification as neuroendocrine tumors (NET), neuroendocrine carcinomas (NEC) and mixed neuroendocrine-non neuroendocrine neoplasms (MiNENs). NECs and MiNENs are aggressive neoplasms requiring multimodal treatment strategies. By contrast, NETs are, in most cases, indolent lesions occurring as incidental findings in the appendix or as polyps in the rectum. While most appendiceal and rectal NETs are considered relatively non-aggressive neoplasms, a few cases, may show a more aggressive clinical course. Unfortunately, clinical/pathological characteristics to select patients at high risk of recurrence/metastases are poorly consolidated. Diagnosis is generally easy and supported by the combination of morphology and immunohistochemistry. Differential diagnostic problems are for NECs/MiNENs with poorly differentiated adenocarcinomas, when immunohistochemical neuroendocrine markers are not obviously positive, whereas for NETs they are represented by the rare appendiceal tubular and clear cell variants (which may be confused with non-neuroendocrine cancers) and rectal L-cell tumors which may be chromogranin negative and prostatic marker positive.
Topics: Appendix; Carcinoma, Neuroendocrine; Colon; Humans; Infant, Newborn; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Rectum
PubMed: 33686307
DOI: 10.32074/1591-951X-230 -
Histopathology Oct 2022The fifth edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems encompasses several updates to the classification and diagnosis of... (Review)
Review
The fifth edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems encompasses several updates to the classification and diagnosis of prostatic carcinoma as well as incorporating advancements in the assessment of its prognosis, including recent grading modifications. Some of the salient aspects include: (1) recognition that prostatic intraepithelial neoplasia (PIN)-like carcinoma is not synonymous with a pattern of ductal carcinoma, but better classified as a subtype of acinar adenocarcinoma; (2) a specific section on treatment-related neuroendocrine prostatic carcinoma in view of the tight correlation between androgen deprivation therapy and the development of prostatic carcinoma with neuroendocrine morphology, and the emerging data on lineage plasticity; (3) a terminology change of basal cell carcinoma to "adenoid cystic (basal cell) cell carcinoma" given the presence of an underlying MYB::NFIB gene fusion in many cases; (4) discussion of the current issues in the grading of acinar adenocarcinoma and the prognostic significance of cribriform growth patterns; and (5) more detailed coverage of intraductal carcinoma of prostate (IDC-P) reflecting our increased knowledge of this entity, while recommending the descriptive term atypical intraductal proliferation (AIP) for lesions falling short of IDC-P but containing more atypia than typically seen in high-grade prostatic intraepithelial neoplasia (HGPIN). Lesions previously regarded as cribriform patterns of HGPIN are now included in the AIP category. This review discusses these developments, summarising the existing literature, as well as the emerging morphological and molecular data that underpins the classification and prognostication of prostatic carcinoma.
Topics: Androgen Antagonists; Carcinoma, Ductal; Humans; Male; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; World Health Organization
PubMed: 35758185
DOI: 10.1111/his.14711 -
Communications Biology Dec 2020Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Although much progress has been made in understanding the development of...
Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Although much progress has been made in understanding the development of neuroendocrine prostate cancer, the cellular architecture associated with neuroendocrine differentiation in human prostate cancer remain incompletely understood. Here, we use single-cell RNA sequencing to profile the transcriptomes of 21,292 cells from needle biopsies of 6 castration-resistant prostate cancers. Our analyses reveal that all neuroendocrine tumor cells display a luminal-like epithelial phenotype. In particular, lineage trajectory analysis suggests that focal neuroendocrine differentiation exclusively originate from luminal-like malignant cells rather than basal compartment. Further tissue microarray analysis validates the generality of the luminal phenotype of neuroendocrine cells. Moreover, we uncover neuroendocrine differentiation-associated gene signatures that may help us to further explore other intrinsic molecular mechanisms deriving neuroendocrine prostate cancer. In summary, our single-cell study provides direct evidence into the cellular states underlying neuroendocrine transdifferentiation in human prostate cancer.
Topics: Aged; Aged, 80 and over; Biopsy; Carcinoma, Neuroendocrine; Cell Line, Tumor; Computational Biology; Epithelial-Mesenchymal Transition; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Neuroendocrine Cells; Prostatic Neoplasms; Single-Cell Analysis; Transcriptome
PubMed: 33328604
DOI: 10.1038/s42003-020-01476-1 -
Pathologica Mar 2020Intraductal carcinoma of the prostate (IDC-P) is a diagnostic entity characterized by architecturally or cytologically malignant-appearing prostatic glandular epithelium... (Review)
Review
Intraductal carcinoma of the prostate (IDC-P) is a diagnostic entity characterized by architecturally or cytologically malignant-appearing prostatic glandular epithelium confined to prostatic ducts. Despite its apparent nature, this lesion is associated with aggressive prostatic adenocarcinoma and is a predictor for poor prognosis when identified on biopsy or radical prostatectomy. This review discusses diagnosis, clinical features, histogenesis, and management of IDC-P, as well as current research and controversies surrounding this entity.
Topics: Carcinoma, Intraductal, Noninfiltrating; Diagnosis, Differential; Humans; Male; Prostatectomy; Prostatic Neoplasms
PubMed: 32202536
DOI: 10.32074/1591-951X-5-20 -
International Journal of Molecular... May 2023Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neoplasms and has extremely poorer prognosis than the typical androgen receptor...
Spatial Gene Expression Analysis Reveals Characteristic Gene Expression Patterns of De Novo Neuroendocrine Prostate Cancer Coexisting with Androgen Receptor Pathway Prostate Cancer.
Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neoplasms and has extremely poorer prognosis than the typical androgen receptor pathway-positive adenocarcinoma of the prostate (ARPC). However, very few cases in which de novo NEPC and APRC are diagnosed simultaneously in the same tissue have been reported. We report herein a 78-year-old man of de novo metastatic NEPC coexisting with ARPC treated at Ehime University Hospital. Visium CytAssist Spatial Gene Expression analysis (10× genetics) was performed using formalin-fixed, paraffin-embedded (FFPE) samples. The neuroendocrine signatures were upregulated in NEPC sites, and androgen receptor signatures were upregulated in ARPC sites. TP53, RB1, or PTEN and upregulation of the homologous recombination repair genes at NEPC sites were not downregulated. Urothelial carcinoma markers were not elevated. Meanwhile, Rbfox3 and SFRTM2 levels were downregulated while the levels of the fibrosis markers HGF, HMOX1, ELN, and GREM1 were upregulated in the tumor microenvironment of NEPC. In conclusion, the findings of spatial gene expression analysis in a patient with coexisting ARPC and de novo NEPC are reported. The accumulation of cases and basic data will help with the development of novel treatments for NEPC and improve the prognosis of patients with castration-resistant prostate cancer.
Topics: Aged; Humans; Male; Carcinoma, Neuroendocrine; Carcinoma, Transitional Cell; Gene Expression; Gene Expression Profiling; Prostatic Neoplasms; Receptors, Androgen; Tumor Microenvironment; Urinary Bladder Neoplasms
PubMed: 37240308
DOI: 10.3390/ijms24108955